EAS Reactions (3) – Friedel-Crafts Acylation and Friedel-Crafts Alkylation

1. Quick Recap On Electrophilic Aromatic Substitution: Onward To Carbon-Carbon Bond Forming Reactions!

This is the third in a series of three posts on the key electrophilic aromatic substitution (EAS) reactions in introductory organic chemistry.

In Part 1 we covered halogenation (chlorination, bromination, and iodination) of aromatic rings via EAS.
In Part 2 we covered nitration and sulfonylation of aromatic rings via EAS.

Taken together, so far we have learned reactions to form carbon-halogen, carbon-nitrogen, and carbon-sulfur bonds.

What important class of bond is missing so far?

Carbon-carbon bond forming reactions! [Note 1]

In this post, we’ll cover two important C–C bond-forming electrophilic aromatic substitution reactions which bear the names of their discoverers, Charles Friedel and James Crafts: Friedel-Crafts alkylation and Friedel-Crafts acylation.

We’ll also see that these reactions follow the familiar three-step pattern seen in previous electrophilic aromatic substitution reactions, namely:

activation of electrophile with a Lewis acid
attack of the “activated” electrophile by the aromatic ring
deprotonation to restore aromaticity

2. Friedel-Crafts Alkylation Of Aromatic Rings

When an alkyl halide is treated with a Lewis acid in the presence of an aromatic ring, the alkyl group can be added to the ring (forming C-C) with the loss of a C-H bond. This electrophilic aromatic substitution reaction is known as the Friedel-Crafts alkylation reaction.

Generally, no reaction occurs in the absence of Lewis acid. A common choice for the Lewis acid is aluminum chloride, AlCl₃ , but many others may be used, such as FeCl₃ among others.

Alkyl halides (typically chlorides, bromides, and iodides) must be used, as the reaction fails completely for alkenyl and alkynyl halides.

Here’s a specific example using ethyl chloride:

3. The Role of The Lewis Acid In Friedel-Crafts Alkylation Is To Activate The Alkyl Halide

If no reaction occurs in the absence of a Lewis acid, then what is the role of the Lewis acid here?

Like we saw in the two previous posts on electrophilic aromatic substitution reactions, Lewis acids “activate” the electrophile by coordinating to the leaving group, making it a weaker base, and a better leaving group (AlCl₄ – is a weaker base than Cl – ). The end result is that coordination of the Lewis acid to the electrophile makes the species a better electrophile.

For example, with isopropyl chloride (below), the first step is coordination of coordination of AlCl₃ to the chlorine atom. This weakens the C-Cl bond, with the result that the Cl can depart (as AlCl₄ – ) to give a secondary carbocation (a better electrophile than isopropyl chloride itself).

With secondary and tertiary halides, full dissociation to a carbocation can occur.
In the case of primary (and methyl) alkyl halides, the electrophile is likely not a “free” carbocation, but a “carbocation-like” species where the C–Cl bond is considerably weakened/lengthened.
As we mentioned briefly, no reaction occurs with alkenyl or alkynyl halides, largely because the carbocations of these species are so unstable and difficult to generate.

Note: that although here we are showing the carbocation electrophile in the Friedel-Crafts as being generated from an alkyl halide and a Lewis acid, there are other ways to generate a carbocation [such as through protonation of an alkene, see below]. We generally define the Friedel-Crafts alkylation as being the reaction of an aromatic ring with a carbocation (or carbocation-like) intermediate. See Note 2 for example.

4. The Key C-C Bond Forming Step Is Attack Of The Aromatic Ring Upon The Carbocation (or carbocation-like) Electrophile

Once the electrophile has been activated, the next step of the Friedel-Crafts is attack of the activated electrophile by the aromatic ring. This is also the rate-determining step, as it disrupts the aromaticity of the ring (and its ~36 kcal/mol of resonance energy).

In this step a C–C (pi) bond from the aromatic ring breaks, and a new C–C sigma bond is formed, leading to a carbocation intermediate:

The last step is deprotonation of C–H by a weak base (e.g. Cl – ) to restore aromaticity at the ring:

[another way to depict the curved arrows in this reaction is to dissociate Cl – from AlCl₄ – and then employ it as the base. Either way it works out to the same thing].

Note that AlCl₃ is regenerated here, allowing it to be used again in step 1 with another equivalent of the alkyl halide. Hence, AlCl₃ can act as a catalyst in this reaction, since it increases the rate of reaction but is not consumed by it.

5. Look Out! Carbocation Rearrangements Can Occur In The Friedel-Crafts Alkylation Reaction

Many university science courses are taught in units, where what you learn in one module has pretty much zero overlap with what you learn in another.

Needless to say, organic chemistry is not like this. You’ve probably already experienced a situation where concepts you learned in Org 1 reverberate back to Org 2 chapters in unexpected ways. Well, get ready for another fun example.

We showed above how ethyl chloride reacts with benzene and AlCl₃ in the Friedel-Crafts alkylation to provide ethylbenzene.

Extension of this reaction from ethyl chloride to propyl chloride should correspondingly give propylbenzene.

What the…. isopropylbenzene?

How did this happen?

Quick trip down memory lane. Remember this beloved reaction from Org 1?

Ah, the hydride shift. Carbocations can rearrange via hydride and alkyl shifts such that a less stable carbocation is transformed into a more stable carbocation.

In the Friedel-Crafts, we’ve seen that coordination of a Lewis acid to an alkyl halide resulted in a carbocation (or in the case of primary alkyl halides, at least a “carbocation-like” species) that is then attacked by the aromatic ring in the rate-determining step.

6. If A Hydride Shift Or Alkyl Shift Will Result In A More Stable Carbocation, It Will Happen

So what is happening here is really no different: if a carbocation can rearrange to a more stable carbocation through a hydride or alkyl shift, it will do so.

Organic chemistry 2: the course where first-semester concepts come back to bite you in the ass.™

Here’s what happens in the case of propyl chloride.

A shift of hydride from C₂ to C₁ results in a secondary carbocation, which is then attacked by the aromatic ring.

Bottom line for the Friedel-Crafts alkylation reaction:

assume the alkyl halide goes through a carbocation
assume that if the carbocation can rearrange to form a more stable carbocation through a hydride (or alkyl) shift, it will.

Another example of a rearrangement in the FC alkylation included in the footnotes just for fun. [Note 3]

7. Limitations of the Freidel-Crafts Alkylation

Final note on the Friedel-Crafts alkylation: a few drawbacks.

First, as we’ve seen, carbocation rearrangements can occur. [There are ways of circumventing this issue indirectly, which we’ll hint at below [skip to bottom].
Second, the Friedel-Crafts alkylation tends not to work well with electron-poor aromatic rings, particularly strongly deactivating substituents such as CF₃, NO₂, SO₃H, and so forth. Halogens are OK.
Third – and this is more of a practical issue than anything else, so is often ignored – the product of the FC alkylation is often a better nucleophile than the starting material. (Recall that alkyl groups are activating.) The result can be a bit like the Cookie Monster in a Chips Ahoy! factory – it can’t stop at just one, resulting in multiple alkylations.

8. Friedel-Crafts Acylation

A process related to the Friedel-Crafts alkylation, called Friedel-Crafts acylation, was discovered by Friedel and Crafts around the same time (1877). If a Lewis acid is added to an acyl halide in the presence of an aromatic ring, an electrophilic aromatic substitution reaction can occur whereby the acyl group adds to the aromatic ring (with loss of HX).

As with the F.C. alkylation, the specific Lewis acid in the Friedel-Crafts acylation can vary. Aluminum chloride (AlCl₃) is often used, but FeCl₃ and other Lewis acids will also do the job.

Here’s a general example of the Friedel-Crafts acylation:

A specific example is the reaction between acetyl chloride and benzene catalyzed by aluminum chloride:

9. The Mechanism Of The Friedel-Crafts Acylation Reaction

So how does the Friedel-Crafts acylation reaction work?

As with FC alkylation, the first step is activation of the electrophile. Lewis acid coordinates to the halogen, and departure of the halogen (as AlCl₄ – ) results in a fairly stable, resonance-stabilized carbocation know as the “acylium ion”.

The acylium ion is the active electrophile in the Friedel-Crafts acylation reaction. Once formed, the acylium ion is attacked by the aromatic ring:

As with the Friedel-Crafts alkylation, the final step is deprotonation at carbon to regenerate the aromatic ring.

10. No Rearrangements Occur In The Friedel-Crafts Acylation

Unlike the Friedel-Crafts alkylation, no rearrangement occurs with the Friedel-Crafts acylation.

This opens up a “workaround” to use the Friedel-Crafts acylation to obtain products that are otherwise difficult to obtain through the Friedel-Crafts alkylation due to carbocation rearrangements. (We’ll talk about this in detail in a future article, but here we’ll just give a taste).

For instance, let’s look at how we could use this to produce propylbenzene, which we saw could not be made from the Friedel-Crafts alkylation reaction of benzene with AlCl₃ and 1-propylchloride.

The first step here is to perform a Friedel-Crafts acylation reaction between benzene and propionylchloride, perhaps catalyzed by AlCl₃. This gives us ethyl phenyl ketone.

The next step is to perform a reduction of the ketone to an alkane, which (as we’ll soon see) can be performed in various ways. This gives us 1-propylbenzene.

[Commenter Victor, from the Chemistry Help Center, helpfully notes that there is a fourth way of doing it – converting the ketone to a thioketal, and then reducing it down to the alkane with Raney nickel. ]

We will talk more about synthetic pathways for aromatic molecules in a future post.

11. Limitations of The Friedel-Crafts Acylation

Similarly to alkylation, Friedel-Crafts acylation tends to fail on aromatic rings with strongly deactivating groups such as nitro, CF₃, sulfonyl and so on. Halogenated aromatics still work, however.
Put this in the “probably don’t need to know category”, but catalyst turnover in the Friedel-Crafts acylation isn’t great. In “real life”, a stoichiometric amount of AlCl₃ is generally required since the AlCl₃ coordinates strongly to the ketone product.

12. Summary: Friedel-Crafts Alkylation and Acylation

Since they form carbon-carbon bonds, the Friedel-Crafts alkylation and acylation reactions are particularly important electrophilic aromatic substitution reactions. Together with bromination, chlorination, nitration, and sulfonylation they round out the six core electrophilic aromatic substitution reactions.

Before we finish our treatment of electrophilic aromatic substitution, it’s worth going into detail on one more facet of the Friedel-Crafts that often gives students headaches; the intramolecular versions.

Notes

Related Articles

Intramolecular Friedel-Crafts Reactions
Aromatic Synthesis (1) – “Order Of Operations”
Synthesis of Benzene Derivatives (2) – Polarity Reversal
Carbocation Rearrangement Reactions (2) – Alkyl Shifts
Friedel-Crafts acylation of aromatic groups to give ketones (MOC Membership)
Friedel Crafts alkylation of arenes (MOC Membership)
Rearrangements in Alkene Addition Reactions

Note 1. Bonus points if you said “carbon-oxygen” as a type of bond we haven’t seen formed in EAS. Direct electrophilic oxygenation of benzene rings is tricky to do in the lab. For our purposes, forming C-O on an aromatic ring is usually done indirectly, by means other than a direct EAS. Two ways we’ll explore in due course are the Baeyer-Villiger oxidation and certain reactions of diazonium salts.

Note 2. Another way of performing a Friedel-Crafts alkylation is to generate the carbocation through protonation of an alkene. This works best when a fairly stable carbocation is generated, such as the t-butyl carbocation generated through protonation of 2-methylpropene.

Note 3. Bonus example with alkyl shift.

Note 4. Last post we learned that sulfonyl groups can be removed with strong acid, and I alluded to another group that can be removed that would be covered in the next post (i.e. this post). That group is t-butyl, which can be removed under forcing conditions, with strong acid. This works because the t-butyl carbocation is relatively stable and the reverse of the Friedel-Crafts alkylation is therefore feasible.

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(Advanced) References and Further Reading

Jie Jack Li describes in his book Name Reactions:
“The discovery of the Friedel–Crafts reaction was the fruit of serendipity and keen observation. In 1877, both Friedel and Crafts were working in Charles A. Wurtz’s laboratory. In order to prepare amyl iodide, they treated amyl chloride with aluminum and iodide using benzene as the solvent. Instead of amyl iodide, they ended up with amylbenzene! Unlike others before them who may have simply discarded the reaction, they thoroughly investigated the Lewis acid-catalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions.”
DOI: 10.1007/978-3-642-01053-8_101
Sur une nouvelle methode generale de synthese d’hydrocarbures, d’acetones, etc.
Friedel and J. M. Crafts
Compt. Rend.187784, 1392-1395
The classic, original paper in French by Friedel and Crafts on the alkylation of aromatics (benzene in this case) with alkyl chlorides with AlCl₃.
REARRANGEMENTS IN THE FRIEDEL-CRAFTS ALKYLATION OF BENZENE
HENRY GILMAN and R. N. MEALS
The Journal of Organic Chemistry1943,08 (2), 126-146
DOI: 10.1021/jo01190a003
This paper by the legendary American Chemist Prof. Henry Gilman (Iowa State) carefully studies the alkylation of benzene by long-chain alkyl halides (C10 and above). This is a monumental effort, especially considering this was prior to modern chromatographic or spectroscopic techniques (e.g. GC or NMR) that would make analysis of mixtures and characterization of these compounds so much easier.George A. Olah, who received the Nobel Prize in Chemistry in 1994, was well-known for his work in superacid and Friedel-Crafts chemistry. Here are a selection of his papers relevant to Friedel-Crafts alkylation:
Aromatic Substitution. VI. Intermediate Complexes and the Reaction Mechanism of Friedel-Crafts Alkylations and Acylations
G. A. Olah and S. J. Kuhn
Journal of the American Chemical Society1958,80 (24), 6541-6545
DOI:10.1021/ja01557a022
Aromatic Substitution. XVI.1 Friedel-Crafts Isopropylation of Benzene and Methylbenzenes with Isopropyl Bromide and Propylene
George A. Olah, Sylvia H. Flood, Stephen J. Kuhn, Maryanne E. Moffatt, and Nina A. Overchuck
Journal of the American Chemical Society1964,86 (6), 1046-1054
DOI:1021/ja01060a016
Aromatic Substitution. XVIII.1 Friedel-Crafts t-Butylation of Benzene and Methylbenzenes with t-Butyl Bromide and Isobutylene
George A. Olah, Sylvia H. Flood, and Maryanne E. Moffatt
Journal of the American Chemical Society1964,86 (6), 1060-1064
DOI:1021/ja01060a018
Aromatic Substitution. XIX.1 Friedel-Crafts Isopropylation and t-Butylation of Halobenzenes
George A. Olah, Sylvia H. Flood, and Maryanne E. Moffatt
Journal of the American Chemical Society1964,86 (6), 1065-1066
DOI:1021/ja01060a019
Aromatic Substitution. XXV.1 Selectivity in the Friedel-Crafts Benzylation, Isopropylation, and t-Butylation of Benzene and Toluene
George A. Olah and Nina A. Overchuk
Journal of the American Chemical Society1965,87 (24), 5786-5788
DOI:1021/ja00952a047
The first sentence in this paper is of note: “Friedel-Crafts alkylations are notorious for their unreliable kinetic behavior”. This is because they are largely heterogeneous, or occur in 2 phases. Also, the footnote indicates that inquiries should be addressed to the Department of Chemistry at the Western Reserve University, Cleveland, OH – before it merged and became Case Western Reserve University.
Aromatic substitution. XXVIII. Mechanism of electrophilic aromatic substitutions
George A. Olah
Acc. Chem. Res.,1971,4 (7), 240-248
DOI:10.1021/ar50043a002
An account by Prof. Olah on the work he had carried out studying the mechanism of various types of electrophilic aromatic substitution reactions – nitration, halogenation, as well as Friedel-Crafts acylation and alkylation.
Aromatic substitution. XXXVII. Stannic and aluminum chloride catalyzed Friedel-Crafts alkylation of naphthalene with alkyl halides. Differentiation of kinetically and thermodynamically controlled product compositions, and the isomerization of alkylnaphthalenes
George A. Olah and Judith A. Olah
Journal of the American Chemical Society1976,98 (7), 1839-1842
DOI:1021/ja00423a032
This is a similar paper by Prof. Olah and his wife, Judith Olah, on the mechanism of Friedel-Crafts alkylation, except using naphthalene instead of benzene. Naphthalene is different in that there are two sites for monosubstitution – the a and b positions.
Friedel-Crafts alkylation of anisole and its comparison with toluene. Predominant ortho-para substitution under kinetic conditions and the effect of thermodynamic isomerizations
George A. Olah, Judith A. Olah, and Toshiyuki Ohyama
Journal of the American Chemical Society1984,106 (18), 5284-5290
DOI:1021/ja00330a042
A surprising sentence in this paper: “No systematic study of the alkylation of anisole was, however, yet reported. Consequently we undertook such a study and report our results”. Sometimes science has these low-hanging fruit, and thoroughly reading the literature can lead you to them.The following papers are related to dealkylation, isomerization, or transfer alkylation under Friedel-Crafts conditions:Friedel-Crafts acylation:
DESOXYBENZOIN
F. H. Allen and W. E. Barker
Org. Synth.1932,12, 16
DOI:10.15227/orgsyn.012.0016
A fairly representative experimental procedure for a Friedel-Crafts acylation in Organic Syntheses, a well-known source for reliable, independently tested synthetic organic experimental laboratory procedures. The product desoxybenzoin would be better known today as dihydrochalcone.
Aromatic Substitution. XXII. Acetylation of Benzene, Alkylbenzenes, and Halobenzenes with Methyloxocarbonium (Acetylium) Hexafluoro- and Hexachloroantimonate
George A. Olah, Stephen J. Kuhn, Sylvia H. Flood, and Barbara A. Hardie
Journal of the American Chemical Society1964,86 (11), 2203-2209
DOI:1021/ja01065a020
This paper deals with the acetylation of aromatics with preformed CH₃CO + salts, which Prof. Olah figured how to isolate using SbF₅. Also, note where these papers were submitted from – Prof. Olah fled from Hungary in the 1950’s to Canada and joined the Dow Chemical Company there.
Aromatic substitution. XXIX. Friedel-Crafts acylation of benzene and toluene with substituted acyl halides. Effect of substituents and positional selectivity
George A. Olah and Shiro Kobayashi
Journal of the American Chemical Society1971,93 (25), 6964-6967
DOI:1021/ja00754a045
This is a mechanistic study of Friedel-Crafts acylation (or ‘benzoylation’ in this case) using the Hammett approach, a classic tool in physical organic chemistry. More reactive electrophiles have lower k_t/k_bratios and low o/p selectivity, while less reactive electrophiles have higher k_t/k_b ratios and higho/p selectivity. k_t/k_bin this case refers to the relative rate of reacting with toluene vs. benzene.Oxygenation (or oxyfunctionalization) of hydrocarbons and aromatics is definitely possible with the right conditions, as the following two papers describe. Prof. George Olah has written a series of papers on the subject.
Oxyfunctionalization of hydrocarbons. 8. Electrophilic hydroxylation of benzene, alkylbenzenes, and halobenzenes with hydrogen peroxide in superacids
George A. Olah and Ryuichiro Ohnishi
The Journal of Organic Chemistry1978,43 (5), 865-867
DOI:1021/jo00399a014
Oxyfunctionalization of hydrocarbons. 14. Electrophilic hydroxylation of aromatics with bis(trimethylsilyl) peroxide/triflic acid
George A. Olah and Thomas D. Ernst
The Journal of Organic Chemistry1989,54 (5), 1204-1206
DOI:1021/jo00266a041
In this paper, bis(trimethylsilyl)peroxide (TMSOOTMS) is used as the oxidant.

00 General Chemistry Review

Lewis Structures
Ionic and Covalent Bonding
Chemical Kinetics
Chemical Equilibria
Valence Electrons of the First Row Elements
How Concepts Build Up In Org 1 ("The Pyramid")

01 Bonding, Structure, and Resonance

How Do We Know Methane (CH4) Is Tetrahedral?
Hybrid Orbitals and Hybridization
How To Determine Hybridization: A Shortcut
Orbital Hybridization And Bond Strengths
Sigma bonds come in six varieties: Pi bonds come in one
A Key Skill: How to Calculate Formal Charge
The Four Intermolecular Forces and How They Affect Boiling Points
3 Trends That Affect Boiling Points
How To Use Electronegativity To Determine Electron Density (and why NOT to trust formal charge)
Introduction to Resonance
How To Use Curved Arrows To Interchange Resonance Forms
Evaluating Resonance Forms (1) - The Rule of Least Charges
How To Find The Best Resonance Structure By Applying Electronegativity
Evaluating Resonance Structures With Negative Charges
Evaluating Resonance Structures With Positive Charge
Exploring Resonance: Pi-Donation
Exploring Resonance: Pi-acceptors
In Summary: Evaluating Resonance Structures
Drawing Resonance Structures: 3 Common Mistakes To Avoid
How to apply electronegativity and resonance to understand reactivity
Bond Hybridization Practice
Structure and Bonding Practice Quizzes
Resonance Structures Practice

02 Acid Base Reactions

Introduction to Acid-Base Reactions
Acid Base Reactions In Organic Chemistry
The Stronger The Acid, The Weaker The Conjugate Base
Walkthrough of Acid-Base Reactions (3) - Acidity Trends
Five Key Factors That Influence Acidity
Acid-Base Reactions: Introducing Ka and pKa
How to Use a pKa Table
The pKa Table Is Your Friend
A Handy Rule of Thumb for Acid-Base Reactions
Acid Base Reactions Are Fast
pKa Values Span 60 Orders Of Magnitude
How Protonation and Deprotonation Affect Reactivity
Acid Base Practice Problems

03 Alkanes and Nomenclature

Meet the (Most Important) Functional Groups
Condensed Formulas: Deciphering What the Brackets Mean
Hidden Hydrogens, Hidden Lone Pairs, Hidden Counterions
Don't Be Futyl, Learn The Butyls
Primary, Secondary, Tertiary, Quaternary In Organic Chemistry
Branching, and Its Affect On Melting and Boiling Points
The Many, Many Ways of Drawing Butane
Wedge And Dash Convention For Tetrahedral Carbon
Common Mistakes in Organic Chemistry: Pentavalent Carbon
Table of Functional Group Priorities for Nomenclature
Summary Sheet - Alkane Nomenclature
Organic Chemistry IUPAC Nomenclature Demystified With A Simple Puzzle Piece Approach
Boiling Point Quizzes
Organic Chemistry Nomenclature Quizzes

04 Conformations and Cycloalkanes

Staggered vs Eclipsed Conformations of Ethane
Conformational Isomers of Propane
Newman Projection of Butane (and Gauche Conformation)
Introduction to Cycloalkanes (1)
Geometric Isomers In Small Rings: Cis And Trans Cycloalkanes
Calculation of Ring Strain In Cycloalkanes
Cycloalkanes - Ring Strain In Cyclopropane And Cyclobutane
Cyclohexane Conformations
Cyclohexane Chair Conformation: An Aerial Tour
How To Draw The Cyclohexane Chair Conformation
The Cyclohexane Chair Flip
The Cyclohexane Chair Flip - Energy Diagram
Substituted Cyclohexanes - Axial vs Equatorial
Ranking The Bulkiness Of Substituents On Cyclohexanes: "A-Values"
Cyclohexane Chair Conformation Stability: Which One Is Lower Energy?
Fused Rings - Cis-Decalin and Trans-Decalin
Naming Bicyclic Compounds - Fused, Bridged, and Spiro
Bredt's Rule (And Summary of Cycloalkanes)
Newman Projection Practice
Cycloalkanes Practice Problems

05 A Primer On Organic Reactions

The Most Important Question To Ask When Learning a New Reaction
Learning New Reactions: How Do The Electrons Move?
The Third Most Important Question to Ask When Learning A New Reaction
7 Factors that stabilize negative charge in organic chemistry
7 Factors That Stabilize Positive Charge in Organic Chemistry
Nucleophiles and Electrophiles
Curved Arrows (for reactions)
Curved Arrows (2): Initial Tails and Final Heads
Nucleophilicity vs. Basicity
The Three Classes of Nucleophiles
What Makes A Good Nucleophile?
What makes a good leaving group?
3 Factors That Stabilize Carbocations
Equilibrium and Energy Relationships
What's a Transition State?
Hammond's Postulate
Learning Organic Chemistry Reactions: A Checklist (PDF)
Introduction to Free Radical Substitution Reactions
Introduction to Oxidative Cleavage Reactions

06 Free Radical Reactions

Bond Dissociation Energies = Homolytic Cleavage
Free Radical Reactions
3 Factors That Stabilize Free Radicals
What Factors Destabilize Free Radicals?
Bond Strengths And Radical Stability
Free Radical Initiation: Why Is "Light" Or "Heat" Required?
Initiation, Propagation, Termination
Monochlorination Products Of Propane, Pentane, And Other Alkanes
Selectivity In Free Radical Reactions
Selectivity in Free Radical Reactions: Bromination vs. Chlorination
Halogenation At Tiffany's
Allylic Bromination
Bonus Topic: Allylic Rearrangements
In Summary: Free Radicals
Synthesis (2) - Reactions of Alkanes
Free Radicals Practice Quizzes

07 Stereochemistry and Chirality

Types of Isomers: Constitutional Isomers, Stereoisomers, Enantiomers, and Diastereomers
How To Draw The Enantiomer Of A Chiral Molecule
How To Draw A Bond Rotation
Introduction to Assigning (R) and (S): The Cahn-Ingold-Prelog Rules
Assigning Cahn-Ingold-Prelog (CIP) Priorities (2) - The Method of Dots
Enantiomers vs Diastereomers vs The Same? Two Methods For Solving Problems
Assigning R/S To Newman Projections (And Converting Newman To Line Diagrams)
How To Determine R and S Configurations On A Fischer Projection
The Meso Trap
Optical Rotation, Optical Activity, and Specific Rotation
Optical Purity and Enantiomeric Excess
What's a Racemic Mixture?
Chiral Allenes And Chiral Axes
Stereochemistry Practice Problems and Quizzes

08 Substitution Reactions

Introduction to Nucleophilic Substitution Reactions
Walkthrough of Substitution Reactions (1) - Introduction
Two Types of Nucleophilic Substitution Reactions
The SN2 Mechanism
Why the SN2 Reaction Is Powerful
The SN1 Mechanism
The Conjugate Acid Is A Better Leaving Group
Comparing the SN1 and SN2 Reactions
Polar Protic? Polar Aprotic? Nonpolar? All About Solvents
Steric Hindrance is Like a Fat Goalie
Common Blind Spot: Intramolecular Reactions
The Conjugate Base is Always a Stronger Nucleophile
Substitution Practice - SN1
Substitution Practice - SN2

09 Elimination Reactions

Elimination Reactions (1): Introduction And The Key Pattern
Elimination Reactions (2): The Zaitsev Rule
Elimination Reactions Are Favored By Heat
Two Elimination Reaction Patterns
The E1 Reaction
The E2 Mechanism
E1 vs E2: Comparing the E1 and E2 Reactions
Antiperiplanar Relationships: The E2 Reaction and Cyclohexane Rings
Bulky Bases in Elimination Reactions
Comparing the E1 vs SN1 Reactions
Elimination (E1) Reactions With Rearrangements
E1cB - Elimination (Unimolecular) Conjugate Base
Elimination (E1) Practice Problems And Solutions
Elimination (E2) Practice Problems and Solutions

10 Rearrangements

Introduction to Rearrangement Reactions
Rearrangement Reactions (1) - Hydride Shifts
Carbocation Rearrangement Reactions (2) - Alkyl Shifts
Pinacol Rearrangement
The SN1, E1, and Alkene Addition Reactions All Pass Through A Carbocation Intermediate

11 SN1/SN2/E1/E2 Decision

Identifying Where Substitution and Elimination Reactions Happen
Deciding SN1/SN2/E1/E2 (1) - The Substrate
Deciding SN1/SN2/E1/E2 (2) - The Nucleophile/Base
SN1 vs E1 and SN2 vs E2 : The Temperature
Deciding SN1/SN2/E1/E2 - The Solvent
Wrapup: The Key Factors For Determining SN1/SN2/E1/E2
Alkyl Halide Reaction Map And Summary
SN1 SN2 E1 E2 Practice Problems

12 Alkene Reactions

E and Z Notation For Alkenes (+ Cis/Trans)
Alkene Stability
Alkene Addition Reactions: "Regioselectivity" and "Stereoselectivity" (Syn/Anti)
Stereoselective and Stereospecific Reactions
Hydrohalogenation of Alkenes and Markovnikov's Rule
Hydration of Alkenes With Aqueous Acid
Rearrangements in Alkene Addition Reactions
Halogenation of Alkenes and Halohydrin Formation
Oxymercuration Demercuration of Alkenes
Hydroboration Oxidation of Alkenes
m-CPBA (meta-chloroperoxybenzoic acid)
OsO4 (Osmium Tetroxide) for Dihydroxylation of Alkenes
Palladium on Carbon (Pd/C) for Catalytic Hydrogenation of Alkenes
Cyclopropanation of Alkenes
A Fourth Alkene Addition Pattern - Free Radical Addition
Alkene Reactions: Ozonolysis
Summary: Three Key Families Of Alkene Reaction Mechanisms
Synthesis (4) - Alkene Reaction Map, Including Alkyl Halide Reactions
Alkene Reactions Practice Problems

13 Alkyne Reactions

Acetylides from Alkynes, And Substitution Reactions of Acetylides
Partial Reduction of Alkynes With Lindlar's Catalyst
Partial Reduction of Alkynes With Na/NH3 To Obtain Trans Alkenes
Alkyne Hydroboration With "R2BH"
Hydration and Oxymercuration of Alkynes
Hydrohalogenation of Alkynes
Alkyne Halogenation: Bromination, Chlorination, and Iodination of Alkynes
Alkyne Reactions - The "Concerted" Pathway
Alkenes To Alkynes Via Halogenation And Elimination Reactions
Alkynes Are A Blank Canvas
Synthesis (5) - Reactions of Alkynes
Alkyne Reactions Practice Problems With Answers

14 Alcohols, Epoxides and Ethers

Alcohols - Nomenclature and Properties
Alcohols Can Act As Acids Or Bases (And Why It Matters)
Alcohols - Acidity and Basicity
The Williamson Ether Synthesis
Ethers From Alkenes, Tertiary Alkyl Halides and Alkoxymercuration
Alcohols To Ethers via Acid Catalysis
Cleavage Of Ethers With Acid
Epoxides - The Outlier Of The Ether Family
Opening of Epoxides With Acid
Epoxide Ring Opening With Base
Making Alkyl Halides From Alcohols
Tosylates And Mesylates
PBr3 and SOCl2
Elimination Reactions of Alcohols
Elimination of Alcohols To Alkenes With POCl3
Alcohol Oxidation: "Strong" and "Weak" Oxidants
Demystifying The Mechanisms of Alcohol Oxidations
Protecting Groups For Alcohols
Thiols And Thioethers
Calculating the oxidation state of a carbon
Oxidation and Reduction in Organic Chemistry
Oxidation Ladders
SOCl2 Mechanism For Alcohols To Alkyl Halides: SN2 versus SNi
Alcohol Reactions Roadmap (PDF)
Alcohol Reaction Practice Problems
Epoxide Reaction Quizzes
Oxidation and Reduction Practice Quizzes

15 Organometallics

What's An Organometallic?
Formation of Grignard and Organolithium Reagents
Organometallics Are Strong Bases
Reactions of Grignard Reagents
Protecting Groups In Grignard Reactions
Synthesis Problems Involving Grignard Reagents
Grignard Reactions And Synthesis (2)
Organocuprates (Gilman Reagents): How They're Made
Gilman Reagents (Organocuprates): What They're Used For
The Heck, Suzuki, and Olefin Metathesis Reactions (And Why They Don't Belong In Most Introductory Organic Chemistry Courses)
Reaction Map: Reactions of Organometallics
Grignard Practice Problems

16 Spectroscopy

Degrees of Unsaturation (or IHD, Index of Hydrogen Deficiency)
Conjugation And Color (+ How Bleach Works)
Introduction To UV-Vis Spectroscopy
UV-Vis Spectroscopy: Absorbance of Carbonyls
UV-Vis Spectroscopy: Practice Questions
Bond Vibrations, Infrared Spectroscopy, and the "Ball and Spring" Model
Infrared Spectroscopy: A Quick Primer On Interpreting Spectra
IR Spectroscopy: 4 Practice Problems
1H NMR: How Many Signals?
Homotopic, Enantiotopic, Diastereotopic
Diastereotopic Protons in 1H NMR Spectroscopy: Examples
C13 NMR - How Many Signals
Liquid Gold: Pheromones In Doe Urine
Natural Product Isolation (1) - Extraction
Natural Product Isolation (2) - Purification Techniques, An Overview
Structure Determination Case Study: Deer Tarsal Gland Pheromone

17 Dienes and MO Theory

What To Expect In Organic Chemistry 2
Are these molecules conjugated?
Conjugation And Resonance In Organic Chemistry
Bonding And Antibonding Pi Orbitals
Molecular Orbitals of The Allyl Cation, Allyl Radical, and Allyl Anion
Pi Molecular Orbitals of Butadiene
Reactions of Dienes: 1,2 and 1,4 Addition
Thermodynamic and Kinetic Products
More On 1,2 and 1,4 Additions To Dienes
s-cis and s-trans
The Diels-Alder Reaction
Cyclic Dienes and Dienophiles in the Diels-Alder Reaction
Stereochemistry of the Diels-Alder Reaction
Exo vs Endo Products In The Diels Alder: How To Tell Them Apart
HOMO and LUMO In the Diels Alder Reaction
Why Are Endo vs Exo Products Favored in the Diels-Alder Reaction?
Diels-Alder Reaction: Kinetic and Thermodynamic Control
The Retro Diels-Alder Reaction
The Intramolecular Diels Alder Reaction
Regiochemistry In The Diels-Alder Reaction
The Cope and Claisen Rearrangements
Electrocyclic Reactions
Electrocyclic Ring Opening And Closure (2) - Six (or Eight) Pi Electrons
Diels Alder Practice Problems
Molecular Orbital Theory Practice

18 Aromaticity

Introduction To Aromaticity
Rules For Aromaticity
Huckel's Rule: What Does 4n+2 Mean?
Aromatic, Non-Aromatic, or Antiaromatic? Some Practice Problems
Antiaromatic Compounds and Antiaromaticity
The Pi Molecular Orbitals of Benzene
The Pi Molecular Orbitals of Cyclobutadiene
Frost Circles
Aromaticity Practice Quizzes

19 Reactions of Aromatic Molecules

Electrophilic Aromatic Substitution: Introduction
Activating and Deactivating Groups In Electrophilic Aromatic Substitution
Electrophilic Aromatic Substitution - The Mechanism
Ortho-, Para- and Meta- Directors in Electrophilic Aromatic Substitution
Understanding Ortho, Para, and Meta Directors
Why are halogens ortho- para- directors?
Disubstituted Benzenes: The Strongest Electron-Donor "Wins"
Electrophilic Aromatic Substitutions (1) - Halogenation of Benzene
Electrophilic Aromatic Substitutions (2) - Nitration and Sulfonation
EAS Reactions (3) - Friedel-Crafts Acylation and Friedel-Crafts Alkylation
Intramolecular Friedel-Crafts Reactions
Nucleophilic Aromatic Substitution (NAS)
Nucleophilic Aromatic Substitution (2) - The Benzyne Mechanism
Reactions on the "Benzylic" Carbon: Bromination And Oxidation
The Wolff-Kishner, Clemmensen, And Other Carbonyl Reductions
More Reactions on the Aromatic Sidechain: Reduction of Nitro Groups and the Baeyer Villiger
Aromatic Synthesis (1) - "Order Of Operations"
Synthesis of Benzene Derivatives (2) - Polarity Reversal
Aromatic Synthesis (3) - Sulfonyl Blocking Groups
Birch Reduction
Synthesis (7): Reaction Map of Benzene and Related Aromatic Compounds
Aromatic Reactions and Synthesis Practice
Electrophilic Aromatic Substitution Practice Problems

20 Aldehydes and Ketones

What's The Alpha Carbon In Carbonyl Compounds?
Nucleophilic Addition To Carbonyls
Aldehydes and Ketones: 14 Reactions With The Same Mechanism
Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones
Grignard Reagents For Addition To Aldehydes and Ketones
Wittig Reaction
Hydrates, Hemiacetals, and Acetals
Imines - Properties, Formation, Reactions, and Mechanisms
All About Enamines
Breaking Down Carbonyl Reaction Mechanisms: Reactions of Anionic Nucleophiles (Part 2)
Aldehydes Ketones Reaction Practice

21 Carboxylic Acid Derivatives

Nucleophilic Acyl Substitution (With Negatively Charged Nucleophiles)
Addition-Elimination Mechanisms With Neutral Nucleophiles (Including Acid Catalysis)
Basic Hydrolysis of Esters - Saponification
Transesterification
Proton Transfer
Fischer Esterification - Carboxylic Acid to Ester Under Acidic Conditions
Lithium Aluminum Hydride (LiAlH4) For Reduction of Carboxylic Acid Derivatives
LiAlH[Ot-Bu]3 For The Reduction of Acid Halides To Aldehydes
Di-isobutyl Aluminum Hydride (DIBAL) For The Partial Reduction of Esters and Nitriles
Amide Hydrolysis
Thionyl Chloride (SOCl2)
Diazomethane (CH2N2)
Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One
Making Music With Mechanisms (PADPED)
Carboxylic Acid Derivatives Practice Questions

22 Enols and Enolates

Keto-Enol Tautomerism
Enolates - Formation, Stability, and Simple Reactions
Kinetic Versus Thermodynamic Enolates
Aldol Addition and Condensation Reactions
Reactions of Enols - Acid-Catalyzed Aldol, Halogenation, and Mannich Reactions
Claisen Condensation and Dieckmann Condensation
Decarboxylation
The Malonic Ester and Acetoacetic Ester Synthesis
The Michael Addition Reaction and Conjugate Addition
The Robinson Annulation
Haloform Reaction
The Hell–Volhard–Zelinsky Reaction
Enols and Enolates Practice Quizzes

23 Amines

The Amide Functional Group: Properties, Synthesis, and Nomenclature
Basicity of Amines And pKaH
5 Key Basicity Trends of Amines
The Mesomeric Effect And Aromatic Amines
Nucleophilicity of Amines
Alkylation of Amines (Sucks!)
Reductive Amination
The Gabriel Synthesis
Some Reactions of Azides
The Hofmann Elimination
The Hofmann and Curtius Rearrangements
The Cope Elimination
Protecting Groups for Amines - Carbamates
The Strecker Synthesis of Amino Acids
Introduction to Peptide Synthesis
Reactions of Diazonium Salts: Sandmeyer and Related Reactions
Amine Practice Questions

24 Carbohydrates

D and L Notation For Sugars
Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
What is Mutarotation?
Reducing Sugars
The Big Damn Post Of Carbohydrate-Related Chemistry Definitions
The Haworth Projection
Converting a Fischer Projection To A Haworth (And Vice Versa)
Reactions of Sugars: Glycosylation and Protection
The Ruff Degradation and Kiliani-Fischer Synthesis
Isoelectric Points of Amino Acids (and How To Calculate Them)
Carbohydrates Practice
Amino Acid Quizzes

25 Fun and Miscellaneous

A Gallery of Some Interesting Molecules From Nature
Screw Organic Chemistry, I'm Just Going To Write About Cats
On Cats, Part 1: Conformations and Configurations
On Cats, Part 2: Cat Line Diagrams
On Cats, Part 4: Enantiocats
On Cats, Part 6: Stereocenters
Organic Chemistry Is Shit
The Organic Chemistry Behind "The Pill"
Maybe they should call them, "Formal Wins" ?
Why Do Organic Chemists Use Kilocalories?
The Principle of Least Effort
Organic Chemistry GIFS - Resonance Forms
Reproducibility In Organic Chemistry
What Holds The Nucleus Together?
How Reactions Are Like Music
Organic Chemistry and the New MCAT

26 Organic Chemistry Tips and Tricks

Common Mistakes: Formal Charges Can Mislead
Partial Charges Give Clues About Electron Flow
Draw The Ugly Version First
Organic Chemistry Study Tips: Learn the Trends
The 8 Types of Arrows In Organic Chemistry, Explained
Top 10 Skills To Master Before An Organic Chemistry 2 Final
Common Mistakes with Carbonyls: Carboxylic Acids. Are Acids!
Planning Organic Synthesis With "Reaction Maps"
Alkene Addition Pattern #1: The "Carbocation Pathway"
Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
Alkene Addition Pattern #3: The "Concerted" Pathway
Number Your Carbons!
The 4 Major Classes of Reactions in Org 1
How (and why) electrons flow
Grossman's Rule
Three Exam Tips
A 3-Step Method For Thinking Through Synthesis Problems
Putting It Together
Putting Diels-Alder Products in Perspective
The Ups and Downs of Cyclohexanes
The Most Annoying Exceptions in Org 1 (Part 1)
The Most Annoying Exceptions in Org 1 (Part 2)
The Marriage May Be Bad, But the Divorce Still Costs Money
9 Nomenclature Conventions To Know
Nucleophile attacks Electrophile

27 Case Studies of Successful O-Chem Students

Success Stories: How Corina Got The The "Hard" Professor - And Got An A+ Anyway
How Helena Aced Organic Chemistry
From a "Drop" To B+ in Org 2 – How A Hard Working Student Turned It Around
How Serge Aced Organic Chemistry
Success Stories: How Zach Aced Organic Chemistry 1
Success Stories: How Kari Went From C– to B+
How Esther Bounced Back From a "C" To Get A's In Organic Chemistry 1 And 2
How Tyrell Got The Highest Grade In Her Organic Chemistry Course
This Is Why Students Use Flashcards
Success Stories: How Stu Aced Organic Chemistry
How John Pulled Up His Organic Chemistry Exam Grades
Success Stories: How Nathan Aced Organic Chemistry (Without It Taking Over His Life)
How Chris Aced Org 1 and Org 2
Interview: How Jay Got an A+ In Organic Chemistry
How to Do Well in Organic Chemistry: One Student's Advice
"America's Top TA" Shares His Secrets For Teaching O-Chem
"Organic Chemistry Is Like. " - A Few Metaphors
How To Do Well In Organic Chemistry: Advice From A Tutor
Guest post: "I went from being afraid of tests to actually looking forward to them".